Identification and in Vivo Evaluation of Liver X Receptor β-Selective Agonists for the Potential Treatment of Alzheimer’s Disease

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• 作者：Shawn J. Stachel ; Celina Zerbinatti ; Michael T. Rudd ; Mali Cosden ; Sokreine Suon ; Kausik K. Nanda ; Keith Wessner ; Jillian DiMuzio ; Jill Maxwell ; Zhenhua Wu ; Jason M. Uslaner ; Maria S. Michener ; Peter Szczerba ; Edward Brnardic ; Vanessa Rada ; Yuntae Kim ; Robert Meissner ; Peter Wuelfing ; Yang Yuan ; Jeanine Ballard ; Marie Holahan ; Daniel J. Klein ; Jun Lu ; Xavier Fradera ; Gopal Parthasarathy ; Victor N. Uebele ; Zhongguo Chen ; Yingjie Li ; Jian Li ; Andrew J. Cooke ; D. Jonathan Bennett ; Mark T. Bilodeau ; John Renger
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：April 14, 2016
• 年：2016
• 卷：59
• 期：7
• 页码：3489-3498
• 全文大小：489K
• 年卷期：0
• ISSN：1520-4804

文摘

Herein, we describe the development of a functionally selective liver X receptor β (LXRβ) agonist series optimized for Emax selectivity, solubility, and physical properties to allow efficacy and safety studies in vivo. Compound 9 showed central pharmacodynamic effects in rodent models, evidenced by statistically significant increases in apolipoprotein E (apoE) and ATP-binding cassette transporter levels in the brain, along with a greatly improved peripheral lipid safety profile when compared to those of full dual agonists. These findings were replicated by subchronic dosing studies in non-human primates, where cerebrospinal fluid levels of apoE and amyloid-β peptides were increased concomitantly with an improved peripheral lipid profile relative to that of nonselective compounds. These results suggest that optimization of LXR agonists for Emax selectivity may have the potential to circumvent the adverse lipid-related effects of hepatic LXR activity.